Corticotropin releasing hormone (CRH) is a brain hormone which is involved in virtually all behavioral and physiological components of successful primate adaptation to stressful circumstances. Our studies have shown that administration of the CRH antagonist antalarmin to primates blocks social stress induced anxiety, stress hormone secretion and sympathetic nervous system activation. CRH is intimately involved in the human response to stress associated with drug abuse. This hormone functions through interaction with well-characterized CRH receptors in the central nervous system (CNS) and subsequent activation of the hypothalamic-pituitary-adrenal axis. Imaging agents for the quantitation of CRH receptors in the normal, abnormal and drug-altered CNS of conscious humans should thus be valuable tools for drug abuse research. Such imaging studies may provide (a) insight in the fundamental nature of drug action and drug abuse on the CNS, (b) methodologies for the development of clinical correlates with drug receptor dysfunction as adjuncts for diagnoses and (c) the ability to further evaluate the effects of treatment of drug abuse and other disorders such as anxiety and depression. In addition, CRH receptor imaging methodology should be of value in the development of novel medications for the treatment of drug abuse and other disorders. Our chemical synthesis program has focused on the design, synthesis and development of CHR receptor imaging agents for positron emission tomography (PET) and single photon emission computed tomography (SPECT) in primates and conscious humans, as well as other related drugs for the CRH system. We have synthesized a number of fluorine and iodine containing ligands as potential PET and SPECT imaging agents, some of which have similar affinity (Ki 0.9-3.5 nM) to the lead compound antalarmin (Ki 2.5 nM). We have labeled one of the fluorine containing compounds with tritium to high specific activity and have shown that this drug enters the rat brain. This compound appears too lipophilic to function as a PET ligand and current studies are focused the identification of a less lipoplilic candidate. We have also synthesized about 2.2 kilograms of antalarmin that has enabled further research in about 25 programs by various groups nationally and internationally. In other areas, we have continued the design, chemical synthesis and biological study of new drugs as potential research tools and medications for the treatment and prevention of opiate, cocaine, methamphetamine and cannabinoid abuse. This work resulted in new oxygenated derivatives of indatraline as potential ultra long acting cocaine and methamphetamine treatment agents. Other advances include the development of a practical nonchromatographic chemical synthesis of MDL100,907 (a highly selective 5HT2A antagonist), its enantiomer, and their 3-phenolic derivatives and precursors suitable for the radiochemical synthesis of [11C]labeled PET ligands.